![conference banner](/images/conference-banner.jpeg)
摘要
癌症是全球人口中一个迅速上升的健康问题,这一负担对公共卫生构成重大挑战。目前的化疗药物有不同的局限性,包括耐药性和严重的副作用,它需要一个强有力的方法来获得有前途的抗癌治疗。人们对天然化合物进行了广泛的研究,以确定用于癌症治疗的改进的治疗剂。Withaferin A (WA)是一种在南非醉茄中发现的甾体内酯,具有抗炎、抗氧化、抗血管生成和抗癌特性。多项研究表明,WA治疗通过诱导细胞凋亡、减少血管生成和转移而减轻了多种癌症特征,同时减少了副作用。WA是一种很有前景的治疗多种癌症的药物,它针对多种信号通路。随着最近的更新,当前的综述强调了WA及其分子靶点在不同癌症中的治疗意义。
关键词: Withaferin A,天然化合物,信号,癌症,靶标,癌症治疗。
[1]
Gordaliza M. Natural products as leads to anticancer drugs. Clin Transl Oncol 2007; 9(12): 767-76.
[http://dx.doi.org/10.1007/s12094-007-0138-9] [PMID: 18158980]
[http://dx.doi.org/10.1007/s12094-007-0138-9] [PMID: 18158980]
[2]
Mallipeddi H, Thyagarajan A, Sahu RP. Implications of Withaferin-A for triple-negative breast cancer chemoprevention. Biomed Pharmacother 2021; 134: 111124.
[http://dx.doi.org/10.1016/j.biopha.2020.111124] [PMID: 33434782]
[http://dx.doi.org/10.1016/j.biopha.2020.111124] [PMID: 33434782]
[3]
Newman DJ, Cragg GM, Snader KM. Natural products as sources of new drugs over the period 1981-2002. J Nat Prod 2003; 66(7): 1022-37.
[http://dx.doi.org/10.1021/np030096l] [PMID: 12880330]
[http://dx.doi.org/10.1021/np030096l] [PMID: 12880330]
[4]
Mishra L-C, Singh BB, Dagenais S. Scientific basis for the therapeutic use of Withania somnifera (ashwagandha): A review. Altern Med Rev 2000; 5(4): 334-46.
[PMID: 10956379]
[PMID: 10956379]
[5]
Shohat B, Gitter S, Abraham A, Lavie D. Antitumor activity of withaferin A (NSC-101088). Cancer Chemother Rep 1967; 51(5): 271-6.
[PMID: 6062297]
[PMID: 6062297]
[6]
Kulkarni SK, Dhir A. Withania somnifera: An Indian ginseng. Prog Neuropsychopharmacol Biol Psychiatry 2008; 32(5): 1093-105.
[http://dx.doi.org/10.1016/j.pnpbp.2007.09.011] [PMID: 17959291]
[http://dx.doi.org/10.1016/j.pnpbp.2007.09.011] [PMID: 17959291]
[7]
Jayaprakasam B, Zhang Y, Seeram NP, Nair MG. Growth inhibition of human tumor cell lines by withanolides from Withania somnifera leaves. Life Sci 2003; 74(1): 125-32.
[http://dx.doi.org/10.1016/j.lfs.2003.07.007] [PMID: 14575818]
[http://dx.doi.org/10.1016/j.lfs.2003.07.007] [PMID: 14575818]
[8]
Ichikawa H, Takada Y, Shishodia S, Jayaprakasam B, Nair MG, Aggarwal BB. Withanolides potentiate apoptosis, inhibit invasion, and abolish osteoclastogenesis through suppression of nuclear factor-κB (NF-κB) activation and NF-κB–regulated gene expression. Mol Cancer Ther 2006; 5(6): 1434-45.
[http://dx.doi.org/10.1158/1535-7163.MCT-06-0096] [PMID: 16818501]
[http://dx.doi.org/10.1158/1535-7163.MCT-06-0096] [PMID: 16818501]
[9]
Choi BY, Kim BW. Withaferin-A inhibits colon cancer cell growth by blocking STAT3 transcriptional activity. J Cancer Prev 2015; 20(3): 185-92.
[http://dx.doi.org/10.15430/JCP.2015.20.3.185] [PMID: 26473157]
[http://dx.doi.org/10.15430/JCP.2015.20.3.185] [PMID: 26473157]
[10]
Ghosh K, De S, Das S, Mukherjee S, Sengupta Bandyopadhyay S. Withaferin A induces ROS-mediated paraptosis in human breast cancer cell-lines MCF-7 and MDA-MB-231. PLoS One 2016; 11(12): e0168488.
[http://dx.doi.org/10.1371/journal.pone.0168488] [PMID: 28033383]
[http://dx.doi.org/10.1371/journal.pone.0168488] [PMID: 28033383]
[11]
Cai Y, Sheng ZY, Chen Y, Bai C. Effect of Withaferin A on A549 cellular proliferation and apoptosis in non-small cell lung cancer. Asian Pac J Cancer Prev 2014; 15(4): 1711-4.
[http://dx.doi.org/10.7314/APJCP.2014.15.4.1711] [PMID: 24641396]
[http://dx.doi.org/10.7314/APJCP.2014.15.4.1711] [PMID: 24641396]
[12]
Kakar SS, Parte S, Carter K, et al. Withaferin A (WFA) inhibits tumor growth and metastasis by targeting ovarian cancer stem cells. Oncotarget 2017; 8(43): 74494-505.
[http://dx.doi.org/10.18632/oncotarget.20170] [PMID: 29088802]
[http://dx.doi.org/10.18632/oncotarget.20170] [PMID: 29088802]
[13]
Moselhy J, Suman S, Alghamdi M, et al. Withaferin A inhibits prostate carcinogenesis in a PTEN-deficient mouse model of prostate cancer. Neoplasia 2017; 19(6): 451-9.
[http://dx.doi.org/10.1016/j.neo.2017.04.005] [PMID: 28494348]
[http://dx.doi.org/10.1016/j.neo.2017.04.005] [PMID: 28494348]
[14]
Liu X, Li Y, Ma Q, Wang Y, Song AL. Withaferin-A inhibits growth of drug-resistant breast carcinoma by inducing apoptosis and autophagy, endogenous reactive oxygen species (ROS) production, and inhibition of cell migration and nuclear factor kappa B (Nf-κB)/mammalian target of rapamycin (m-TOR) signalling pathway. Med Sci Monit 2019; 25: 6855-63.
[http://dx.doi.org/10.12659/MSM.916931] [PMID: 31512681]
[http://dx.doi.org/10.12659/MSM.916931] [PMID: 31512681]
[15]
Stan SD, Hahm ER, Warin R, Singh SV. Withaferin A causes FOXO3a- and Bim-dependent apoptosis and inhibits growth of human breast cancer cells in vivo. Cancer Res 2008; 68(18): 7661-9.
[http://dx.doi.org/10.1158/0008-5472.CAN-08-1510] [PMID: 18794155]
[http://dx.doi.org/10.1158/0008-5472.CAN-08-1510] [PMID: 18794155]
[16]
Hahm ER, Moura MB, Kelley EE, Van Houten B, Shiva S, Singh SV. Withaferin A-induced apoptosis in human breast cancer cells is mediated by reactive oxygen species. PLoS One 2011; 6(8): e23354.
[http://dx.doi.org/10.1371/journal.pone.0023354] [PMID: 21853114]
[http://dx.doi.org/10.1371/journal.pone.0023354] [PMID: 21853114]
[17]
Sharada AC, Solomon FE, Devi PU, Udupa N, Srinivasan KK. Antitumor and radiosensitizing effects of withaferin A on mouse Ehrlich ascites carcinoma in vivo. Acta Oncol 1996; 35(1): 95-100.
[http://dx.doi.org/10.3109/02841869609098486] [PMID: 8619948]
[http://dx.doi.org/10.3109/02841869609098486] [PMID: 8619948]
[18]
Sultana T, Okla MK, Ahmed M, et al. Withaferin A: From ancient remedy to potential drug candidate. Molecules 2021; 26(24): 7696.
[http://dx.doi.org/10.3390/molecules26247696] [PMID: 34946778]
[http://dx.doi.org/10.3390/molecules26247696] [PMID: 34946778]
[19]
Vanden Berghe W, Sabbe L, Kaileh M, Haegeman G, Heyninck K. Molecular insight in the multifunctional activities of Withaferin A. Biochem Pharmacol 2012; 84(10): 1282-91.
[http://dx.doi.org/10.1016/j.bcp.2012.08.027] [PMID: 22981382]
[http://dx.doi.org/10.1016/j.bcp.2012.08.027] [PMID: 22981382]
[20]
Misra L, Lal P, Chaurasia ND, Sangwan RS, Sinha S, Tuli R. Selective reactivity of 2-mercaptoethanol with 5β, 6β-epoxide in steroids from Withania somnifera. Steroids 2008; 73(3): 245-51.
[21]
Fuska J, Fuskova A, Rosazza J, Nicholas AJN. Novel cytotoxic and antitumor agents. IV. Withaferin A: relation of its structure to the in vitro cytotoxic effects on P388 cells. Neoplasma 1984; 31(1): 31-6.
[22]
Gupta SK, Jadhav S, Gohil D, et al. Safety, toxicity and pharmacokinetic assessment of oral Withaferin-A in mice. Toxicol Rep 2022; 9: 1204-12.
[http://dx.doi.org/10.1016/j.toxrep.2022.05.012]
[http://dx.doi.org/10.1016/j.toxrep.2022.05.012]
[23]
Thaiparambil JT, Bender L, Ganesh T, et al. Withaferin A inhibits breast cancer invasion and metastasis at sub-cytotoxic doses by inducing vimentin disassembly and serine 56 phosphorylation. Int J Cancer 2011; 129(11): 2744-55.
[http://dx.doi.org/10.1002/ijc.25938] [PMID: 21538350]
[http://dx.doi.org/10.1002/ijc.25938] [PMID: 21538350]
[24]
Patil D, Gautam M, Mishra S, et al. Determination of withaferin A and withanolide A in mice plasma using high-performance liquid chromatography-tandem mass spectrometry: Application to pharmacokinetics after oral administration of Withania somnifera aqueous extract. J Pharm Biomed Anal 2013; 80: 203-12.
[http://dx.doi.org/10.1016/j.jpba.2013.03.001] [PMID: 23584079]
[http://dx.doi.org/10.1016/j.jpba.2013.03.001] [PMID: 23584079]
[25]
Dai T, Jiang W, Guo Z, et al. Studies on oral bioavailability and first‐pass metabolism of withaferin A in rats using LC–MS/MS and Q‐TRAP. Biomed Chromatogr 2019; 33(9): e4573.
[http://dx.doi.org/10.1002/bmc.4573] [PMID: 31062367]
[http://dx.doi.org/10.1002/bmc.4573] [PMID: 31062367]
[26]
Pires N, Gota V, Gulia A, et al. Safety and pharmacokinetics of Withaferin-A in advanced stage high grade osteosarcoma: A phase I trial. J Ayurveda Integr Med 2020; 11(1): 68-72.
[http://dx.doi.org/10.1016/j.jaim.2018.12.008]
[http://dx.doi.org/10.1016/j.jaim.2018.12.008]
[27]
Hahm ER, Lee J, Singh SV. Role of mitogen-activated protein kinases and Mcl-1 in apoptosis induction by withaferin A in human breast cancer cells. Mol Carcinog 2014; 53(11): 907-16.
[http://dx.doi.org/10.1002/mc.22050] [PMID: 24019090]
[http://dx.doi.org/10.1002/mc.22050] [PMID: 24019090]
[28]
Samanta SK, Lee J, Hahm ER, Singh SV. Peptidyl-prolyl cis/trans isomerase Pin1 regulates withaferin A-mediated cell cycle arrest in human breast cancer cells. Mol Carcinog 2018; 57(7): 936-46.
[http://dx.doi.org/10.1002/mc.22814] [PMID: 29603395]
[http://dx.doi.org/10.1002/mc.22814] [PMID: 29603395]
[29]
Zúñiga R, Concha G, Cayo A, et al. Withaferin A suppresses breast cancer cell proliferation by inhibition of the two-pore domain potassium (K2P9) channel TASK-3. Biomed Pharmacother 2020; 129: 110383.
[http://dx.doi.org/10.1016/j.biopha.2020.110383] [PMID: 32563149]
[http://dx.doi.org/10.1016/j.biopha.2020.110383] [PMID: 32563149]
[30]
Sehrawat A, Samanta SK, Hahm E-R, St Croix C, Watkins S, Singh SV. Withaferin A-mediated apoptosis in breast cancer cells is associated with alterations in mitochondrial dynamics. Mitochondrion 2019; 47: 282-93.
[http://dx.doi.org/10.1016/j.mito.2019.01.003] [PMID: 30685490]
[http://dx.doi.org/10.1016/j.mito.2019.01.003] [PMID: 30685490]
[31]
Hahm ER, Kim SH, Singh KB, Singh SV. RNA‐seq reveals novel cancer‐selective and disease subtype‐independent mechanistic targets of withaferin A in human breast cancer cells. Mol Carcinog 2021; 60(1): 3-14.
[http://dx.doi.org/10.1002/mc.23266] [PMID: 33150660]
[http://dx.doi.org/10.1002/mc.23266] [PMID: 33150660]
[32]
Samanta SK, Sehrawat A, Kim SH, et al. Disease subtype–independent biomarkers of breast cancer chemoprevention by the ayurvedic medicine phytochemical withaferin A. J Natl Cancer Inst 2017; 109(6): djw293.
[http://dx.doi.org/10.1093/jnci/djw293] [PMID: 28040797]
[http://dx.doi.org/10.1093/jnci/djw293] [PMID: 28040797]
[33]
Kim SH, Kaschula CH, Priedigkeit N, Lee AV, Singh SV. Forkhead box Q1 is a novel target of breast cancer stem cell inhibition by diallyl trisulfide. J Biol Chem 2016; 291(26): 13495-508.
[http://dx.doi.org/10.1074/jbc.M116.715219] [PMID: 27129776]
[http://dx.doi.org/10.1074/jbc.M116.715219] [PMID: 27129776]
[34]
Kim S-H, Singh KB, Hahm E-R, Singh SV. The role of forkhead box Q1 transcription factor in anti-cancer effects of Withaferin A in breast cancerrole of FoxQ1 in bCSC inhibition by Withaferin A. Cancer Prev Res 2021; 14(4): 421-32.
[http://dx.doi.org/10.1158/1940-6207.CAPR-20-0590] [PMID: 33509807]
[http://dx.doi.org/10.1158/1940-6207.CAPR-20-0590] [PMID: 33509807]
[35]
Prajapati KS, Shuaib M, Gupta S, Kumar S. Withaferin A mediated changes of miRNA expression in breast cancer‐derived mammospheres. Mol Carcinog 2022; 61(9): 876-89.
[http://dx.doi.org/10.1002/mc.23440] [PMID: 35770722]
[http://dx.doi.org/10.1002/mc.23440] [PMID: 35770722]
[36]
Kim SH, Singh SV. Mammary cancer chemoprevention by withaferin A is accompanied by in vivo suppression of self-renewal of cancer stem cells. Cancer Prev Res 2014; 7(7): 738-47.
[http://dx.doi.org/10.1158/1940-6207.CAPR-13-0445] [PMID: 24824039]
[http://dx.doi.org/10.1158/1940-6207.CAPR-13-0445] [PMID: 24824039]
[37]
Ali MA, Farah MA, Al-Anazi KM, et al. In Silico Elucidation of the Plausible Inhibitory Potential of Withaferin A of Withania somnifera Medicinal Herb Against Breast Cancer Targeting Estrogen Receptor. Curr Pharm Biotechnol 2020; 21(9): 842-51.
[http://dx.doi.org/10.2174/1389201021666200129121843] [PMID: 31995002]
[http://dx.doi.org/10.2174/1389201021666200129121843] [PMID: 31995002]
[38]
Hahm ER, Lee J, Huang Y, Singh SV. Withaferin a suppresses estrogen receptor-α expression in human breast cancer cells. Mol Carcinog 2011; 50(8): 614-24.
[http://dx.doi.org/10.1002/mc.20760] [PMID: 21432907]
[http://dx.doi.org/10.1002/mc.20760] [PMID: 21432907]
[39]
Zhang X, Mukerji R, Samadi AK, Cohen MS. Down-regulation of estrogen receptor-alpha and rearranged during transfection tyrosine kinase is associated with withaferin a-induced apoptosis in MCF-7 breast cancer cells. BMC Complement Altern Med 2011; 11(1): 84.
[http://dx.doi.org/10.1186/1472-6882-11-84] [PMID: 21978374]
[http://dx.doi.org/10.1186/1472-6882-11-84] [PMID: 21978374]
[40]
Royston KJ, Paul B, Nozell S, Rajbhandari R, Tollefsbol TO. Withaferin A and sulforaphane regulate breast cancer cell cycle progression through epigenetic mechanisms. Exp Cell Res 2018; 368(1): 67-74.
[http://dx.doi.org/10.1016/j.yexcr.2018.04.015] [PMID: 29689276]
[http://dx.doi.org/10.1016/j.yexcr.2018.04.015] [PMID: 29689276]
[41]
Royston K, Udayakumar N, Lewis K, Tollefsbol T. A novel combination of withaferin A and sulforaphane inhibits epigenetic machinery, cellular viability and induces apoptosis of breast cancer cells. Int J Mol Sci 2017; 18(5): 1092.
[http://dx.doi.org/10.3390/ijms18051092] [PMID: 28534825]
[http://dx.doi.org/10.3390/ijms18051092] [PMID: 28534825]
[42]
Hahm ER, Lee J, Abella T, Singh SV. Withaferin A inhibits expression of ataxia telangiectasia and Rad3‐related kinase and enhances sensitivity of human breast cancer cells to cisplatin. Mol Carcinog 2019; 58(11): 2139-48.
[http://dx.doi.org/10.1002/mc.23104] [PMID: 31441116]
[http://dx.doi.org/10.1002/mc.23104] [PMID: 31441116]
[43]
Szarc vel Szic K, Declerck K, Crans RAJ, et al. Epigenetic silencing of triple negative breast cancer hallmarks by Withaferin A. Oncotarget 2017; 8(25): 40434-53.
[http://dx.doi.org/10.18632/oncotarget.17107] [PMID: 28467815]
[http://dx.doi.org/10.18632/oncotarget.17107] [PMID: 28467815]
[44]
Kim SH, Hahm ER, Arlotti JA, et al. Withaferin A inhibits in vivo growth of breast cancer cells accelerated by Notch2 knockdown. Breast Cancer Res Treat 2016; 157(1): 41-54.
[http://dx.doi.org/10.1007/s10549-016-3795-y] [PMID: 27097807]
[http://dx.doi.org/10.1007/s10549-016-3795-y] [PMID: 27097807]
[45]
Lee J, Sehrawat A, Singh SV. Withaferin A causes activation of Notch2 and Notch4 in human breast cancer cells. Breast Cancer Res Treat 2012; 136(1): 45-56.
[http://dx.doi.org/10.1007/s10549-012-2239-6] [PMID: 22965833]
[http://dx.doi.org/10.1007/s10549-012-2239-6] [PMID: 22965833]
[46]
Zhang X, Timmermann B, Samadi AK, Cohen MS. Withaferin A induces proteasome-dependent degradation of breast cancer susceptibility gene 1 and heat shock factor 1 proteins in breast cancer cells. Int Scholarly Res Not 2012.
[http://dx.doi.org/10.5402/2012/707586]
[http://dx.doi.org/10.5402/2012/707586]
[47]
Stan S D, Zeng Y, Singh S V. Ayurvedic medicine constituent withaferin a causes G2 and M phase cell cycle arrest in human breast cancer cells. Nutrition cancer letters 2008; 60(S1): 51-60.
[48]
Ghosh K, De S, Mukherjee S, Das S, Ghosh AN, Sengupta S B J T I V. Withaferin A induced impaired autophagy and unfolded protein response in human breast cancer cell-lines MCF-7 and MDA-MB-231. Toxicol In Vitro 2017; 44: 330-8.
[http://dx.doi.org/10.1016/j.tiv.2017.07.025]
[http://dx.doi.org/10.1016/j.tiv.2017.07.025]
[49]
Hahm ER, Singh SV. Withaferin A-induced apoptosis in human breast cancer cells is associated with suppression of inhibitor of apoptosis family protein expression. Cancer Lett 2013; 334(1): 101-8.
[http://dx.doi.org/10.1016/j.canlet.2012.08.026] [PMID: 22935676]
[http://dx.doi.org/10.1016/j.canlet.2012.08.026] [PMID: 22935676]
[50]
Lee J, Hahm ER, Singh SV. Withaferin A inhibits activation of signal transducer and activator of transcription 3 in human breast cancer cells. Carcinogenesis 2010; 31(11): 1991-8.
[http://dx.doi.org/10.1093/carcin/bgq175] [PMID: 20724373]
[http://dx.doi.org/10.1093/carcin/bgq175] [PMID: 20724373]
[51]
Muniraj N, Siddharth S, Nagalingam A, et al. Withaferin A inhibits lysosomal activity to block autophagic flux and induces apoptosis via energetic impairment in breast cancer cells. Carcinogenesis 2019; 40(9): 1110-20.
[http://dx.doi.org/10.1093/carcin/bgz015] [PMID: 30698683]
[http://dx.doi.org/10.1093/carcin/bgz015] [PMID: 30698683]
[52]
Nagalingam A, Kuppusamy P, Singh SV, Sharma D, Saxena NK. Mechanistic elucidation of the antitumor properties of Withaferin A in breast cancer. Cancer Res 2014; 74(9): 2617-29.
[http://dx.doi.org/10.1158/0008-5472.CAN-13-2081] [PMID: 24732433]
[http://dx.doi.org/10.1158/0008-5472.CAN-13-2081] [PMID: 24732433]
[53]
Lee J, Hahm ER, Marcus AI, Singh SV. Withaferin A inhibits experimental epithelial-mesenchymal transition in MCF-10A cells and suppresses vimentin protein level in vivo in breast tumors. Mol Carcinog 2015; 54(6): 417-29.
[http://dx.doi.org/10.1002/mc.22110] [PMID: 24293234]
[http://dx.doi.org/10.1002/mc.22110] [PMID: 24293234]
[54]
Antony ML, Lee J, Hahm ER, et al. Growth arrest by the antitumor steroidal lactone withaferin A in human breast cancer cells is associated with down-regulation and covalent binding at cysteine 303 of β-tubulin. J Biol Chem 2014; 289(3): 1852-65.
[http://dx.doi.org/10.1074/jbc.M113.496844] [PMID: 24297176]
[http://dx.doi.org/10.1074/jbc.M113.496844] [PMID: 24297176]
[55]
Liu X, Chen L, Liang T, Tian XD, Liu Y, Zhang T. Withaferin A induces mitochondrial-dependent apoptosis in non-small cell lung cancer cells via generation of reactive oxygen species. J BUON 2017; 22(1): 244-50.
[PMID: 28365961]
[PMID: 28365961]
[56]
Lin CC, Yang TY, Lu HJ, Wan CK, Hsu SL, Wu CC. Attenuating role of withaferin A in the proliferation and migration of lung cancer cells via a p53 miR 27a/miR 10b pathway. Oncol Lett 2021; 21(3): 232.
[http://dx.doi.org/10.3892/ol.2021.12493]
[http://dx.doi.org/10.3892/ol.2021.12493]
[57]
Hsu JH-M, Chang PM-H, Cheng T-S, et al. Identification of withaferin A as a potential candidate for anti-cancer therapy in non-small cell lung cancer. Cancers (Basel) 2019; 11(7): 1003.
[http://dx.doi.org/10.3390/cancers11071003] [PMID: 31319622]
[http://dx.doi.org/10.3390/cancers11071003] [PMID: 31319622]
[58]
Kyakulaga AH, Aqil F, Munagala R, Gupta RC. Withaferin A inhibits epithelial to mesenchymal transition in non-small cell lung cancer cells. Sci Rep 2018; 8(1): 15737.
[http://dx.doi.org/10.1038/s41598-018-34018-1] [PMID: 30356176]
[http://dx.doi.org/10.1038/s41598-018-34018-1] [PMID: 30356176]
[59]
Kyakulaga AH, Aqil F, Munagala R, Gupta R. Abstract 2040: Withaferin A inhibits epithelial-to-mesenchymal transition in non-small lung cell cancer cells via regulation of SMAD and NFkB signaling. Cancer Res 2018; 78(13_Supplement)(Suppl.): 2040-0.
[http://dx.doi.org/10.1158/1538-7445.AM2018-2040]
[http://dx.doi.org/10.1158/1538-7445.AM2018-2040]
[60]
Malik V, Kumar V, Kaul SC, Wadhwa R, Sundar D. Computational insights into the potential of withaferin-A, Withanone and caffeic acid phenethyl ester for treatment of aberrant-EGFR driven lung cancers. Biomolecules 2021; 11(2): 160.
[http://dx.doi.org/10.3390/biom11020160] [PMID: 33530424]
[http://dx.doi.org/10.3390/biom11020160] [PMID: 33530424]
[61]
Kyakulaga AH, Aqil F, Munagala R, Gupta RC. Synergistic combinations of paclitaxel and withaferin A against human non-small cell lung cancer cells. Oncotarget 2020; 11(16): 1399-416.
[http://dx.doi.org/10.18632/oncotarget.27519] [PMID: 32362998]
[http://dx.doi.org/10.18632/oncotarget.27519] [PMID: 32362998]
[62]
Zhang X, Samadi AK, Roby KF, Timmermann B, Cohen MS. Inhibition of cell growth and induction of apoptosis in ovarian carcinoma cell lines CaOV3 and SKOV3 by natural withanolide Withaferin A. Gynecol Oncol 2012; 124(3): 606-12.
[http://dx.doi.org/10.1016/j.ygyno.2011.11.044] [PMID: 22188785]
[http://dx.doi.org/10.1016/j.ygyno.2011.11.044] [PMID: 22188785]
[63]
Kakar SS, Worth CA, Wang Z, Carter K, Ratajczak MZ, Gunjal P. DOXIL when combined with Withaferin A (WFA) targets ALDH1 positive cancer stem cells in ovarian cancer. J Cancer Stem Cell Res 2016; 4(2): 1.
[http://dx.doi.org/10.14343/JCSCR.2016.4e1002] [PMID: 27668267]
[http://dx.doi.org/10.14343/JCSCR.2016.4e1002] [PMID: 27668267]
[64]
Kakar SS, Ratajczak MZ, Powell KS, et al. Withaferin a alone and in combination with cisplatin suppresses growth and metastasis of ovarian cancer by targeting putative cancer stem cells. PLoS One 2014; 9(9): e107596.
[http://dx.doi.org/10.1371/journal.pone.0107596] [PMID: 25264898]
[http://dx.doi.org/10.1371/journal.pone.0107596] [PMID: 25264898]
[65]
Fong MY, Jin S, Rane M, Singh RK, Gupta R, Kakar SS. Withaferin A synergizes the therapeutic effect of doxorubicin through ROS-mediated autophagy in ovarian cancer. PLoS One 2012; 7(7): e42265.
[http://dx.doi.org/10.1371/journal.pone.0042265] [PMID: 22860102]
[http://dx.doi.org/10.1371/journal.pone.0042265] [PMID: 22860102]
[66]
Straughn AR, Kelm NQ, Kakar SS. Withaferin a and ovarian cancer antagonistically regulate skeletal muscle mass. Front Cell Dev Biol 2021; 9: 636498.
[http://dx.doi.org/10.3389/fcell.2021.636498] [PMID: 33718372]
[http://dx.doi.org/10.3389/fcell.2021.636498] [PMID: 33718372]
[67]
Kelm NQ, Straughn AR, Kakar SS. Withaferin A attenuates ovarian cancer-induced cardiac cachexia. PLoS One 2020; 15(7): e0236680.
[http://dx.doi.org/10.1371/journal.pone.0236680] [PMID: 32722688]
[http://dx.doi.org/10.1371/journal.pone.0236680] [PMID: 32722688]
[68]
Straughn AR, Kakar SS. Withaferin A ameliorates ovarian cancer-induced cachexia and proinflammatory signaling. J Ovarian Res 2019; 12(1): 115.
[http://dx.doi.org/10.1186/s13048-019-0586-1] [PMID: 31767036]
[http://dx.doi.org/10.1186/s13048-019-0586-1] [PMID: 31767036]
[69]
Yu Y, Hamza A, Zhang T, et al. Withaferin A targets heat shock protein 90 in pancreatic cancer cells. Biochem Pharmacol 2010; 79(4): 542-51.
[http://dx.doi.org/10.1016/j.bcp.2009.09.017] [PMID: 19769945]
[http://dx.doi.org/10.1016/j.bcp.2009.09.017] [PMID: 19769945]
[70]
Li X, Zhu F, Jiang J, et al. Synergistic antitumor activity of withaferin A combined with oxaliplatin triggers reactive oxygen species-mediated inactivation of the PI3K/AKT pathway in human pancreatic cancer cells. Cancer Lett 2015; 357(1): 219-30.
[http://dx.doi.org/10.1016/j.canlet.2014.11.026] [PMID: 25444914]
[http://dx.doi.org/10.1016/j.canlet.2014.11.026] [PMID: 25444914]
[71]
Aliebrahimi S, Kouhsari SM, Arab SS, Shadboorestan A, Ostad SN. Phytochemicals, withaferin A and carnosol, overcome pancreatic cancer stem cells as c-Met inhibitors. Biomed Pharmacother 2018; 106: 1527-36.
[http://dx.doi.org/10.1016/j.biopha.2018.07.055] [PMID: 30119228]
[http://dx.doi.org/10.1016/j.biopha.2018.07.055] [PMID: 30119228]
[72]
Xia S, Miao Y, Liu S. Withaferin A induces apoptosis by ROS-dependent mitochondrial dysfunction in human colorectal cancer cells. Biochem Biophys Res Commun 2018; 503(4): 2363-9.
[http://dx.doi.org/10.1016/j.bbrc.2018.06.162] [PMID: 29966656]
[http://dx.doi.org/10.1016/j.bbrc.2018.06.162] [PMID: 29966656]
[73]
Chandrasekaran B, Pal D, Kolluru V, et al. The chemopreventive effect of withaferin A on spontaneous and inflammation-associated colon carcinogenesis models. Carcinogenesis 2018; 39(12): 1537-47.
[http://dx.doi.org/10.1093/carcin/bgy109] [PMID: 30124785]
[http://dx.doi.org/10.1093/carcin/bgy109] [PMID: 30124785]
[74]
Koduru S, Kumar R, Srinivasan S, Evers MB, Damodaran C. Notch-1 inhibition by Withaferin-A: A therapeutic target against colon carcinogenesis. Mol Cancer Ther 2010; 9(1): 202-10.
[http://dx.doi.org/10.1158/1535-7163.MCT-09-0771] [PMID: 20053782]
[http://dx.doi.org/10.1158/1535-7163.MCT-09-0771] [PMID: 20053782]
[75]
Suman S, Das TP, Sirimulla S, Alatassi H, Ankem MK, Damodaran C. Withaferin-A suppress AKT induced tumor growth in colorectal cancer cells. Oncotarget 2016; 7(12): 13854-64.
[http://dx.doi.org/10.18632/oncotarget.7351] [PMID: 26883103]
[http://dx.doi.org/10.18632/oncotarget.7351] [PMID: 26883103]
[76]
Das T, Roy KS, Chakrabarti T, Mukhopadhyay S, Roychoudhury S. Withaferin A modulates the spindle assembly checkpoint by degradation of Mad2–Cdc20 complex in colorectal cancer cell lines. Biochem Pharmacol 2014; 91(1): 31-9.
[http://dx.doi.org/10.1016/j.bcp.2014.06.022] [PMID: 24995417]
[http://dx.doi.org/10.1016/j.bcp.2014.06.022] [PMID: 24995417]
[77]
Park JW, Min KJ, Kim DE, Kwon TK. Withaferin A induces apoptosis through the generation of thiol oxidation in human head and neck cancer cells. Int J Mol Med 2015; 35(1): 247-52.
[http://dx.doi.org/10.3892/ijmm.2014.1983] [PMID: 25351115]
[http://dx.doi.org/10.3892/ijmm.2014.1983] [PMID: 25351115]
[78]
Lee HE, Shin JA, Jeong JH, Jeon JG, Lee MH, Cho SD. Anticancer activity of Ashwagandha against human head and neck cancer cell lines. J Oral Pathol Med 2016; 45(3): 193-201.
[http://dx.doi.org/10.1111/jop.12353] [PMID: 26332363]
[http://dx.doi.org/10.1111/jop.12353] [PMID: 26332363]
[79]
Samadi AK, Tong X, Mukerji R, et al. Withaferin A, a cytotoxic steroid from Vassobia breviflora, induces apoptosis in human head and neck squamous cell carcinoma. J Nat Prod 2010; 73(9): 1476-81.
[http://dx.doi.org/10.1021/np100112p] [PMID: 20726569]
[http://dx.doi.org/10.1021/np100112p] [PMID: 20726569]
[80]
Yu TJ, Tang JY, Ou-Yang F, et al. Low concentration of withaferin A inhibits oxidative stress-mediated migration and invasion in oral cancer cells. Biomolecules 2020; 10(5): 777.
[http://dx.doi.org/10.3390/biom10050777] [PMID: 32429564]
[http://dx.doi.org/10.3390/biom10050777] [PMID: 32429564]
[81]
Yang IH, Kim LH, Shin JA, Cho SD. Chemotherapeutic effect of withaferin A in human oral cancer cells. J Cancer Ther 2015; 6(8): 735-42.
[http://dx.doi.org/10.4236/jct.2015.68080]
[http://dx.doi.org/10.4236/jct.2015.68080]
[82]
Peng SY, Wang YY, Lan TH, et al. Low dose combined treatment with ultraviolet-C and withaferin a enhances selective killing of oral cancer cells. Antioxidants 2020; 9(11): 1120.
[http://dx.doi.org/10.3390/antiox9111120] [PMID: 33202766]
[http://dx.doi.org/10.3390/antiox9111120] [PMID: 33202766]
[83]
Chang HW, Li RN, Wang HR, et al. Withaferin A induces oxidative stress-mediated apoptosis and DNA damage in oral cancer cells. Front Physiol 2017; 8: 634.
[http://dx.doi.org/10.3389/fphys.2017.00634] [PMID: 28936177]
[http://dx.doi.org/10.3389/fphys.2017.00634] [PMID: 28936177]
[84]
Shin JA, Kim LH, Ryu MH, et al. Withaferin A mitigates metastatic traits in human oral squamous cell carcinoma caused by aberrant claudin-1 expression. Cell Biol Toxicol 2022; 38(1): 147-65.
[http://dx.doi.org/10.1007/s10565-021-09584-2] [PMID: 33665778]
[http://dx.doi.org/10.1007/s10565-021-09584-2] [PMID: 33665778]
[85]
Samadi AK, Mukerji R, Shah A, Timmermann BN, Cohen MS. A novel RET inhibitor with potent efficacy against medullary thyroid cancer in vivo. Surgery 2010; 148(6): 1228-36.
[http://dx.doi.org/10.1016/j.surg.2010.09.026] [PMID: 21134556]
[http://dx.doi.org/10.1016/j.surg.2010.09.026] [PMID: 21134556]
[86]
Cohen SM, Mukerji R, Timmermann BN, Samadi AK, Cohen MS. A novel combination of withaferin A and sorafenib shows synergistic efficacy against both papillary and anaplastic thyroid cancers. Am J Surg 2012; 204(6): 895-901.
[http://dx.doi.org/10.1016/j.amjsurg.2012.07.027] [PMID: 23231932]
[http://dx.doi.org/10.1016/j.amjsurg.2012.07.027] [PMID: 23231932]
[87]
Mayola E, Gallerne C, Esposti DD, et al. Withaferin A induces apoptosis in human melanoma cells through generation of reactive oxygen species and down-regulation of Bcl-2. Apoptosis 2011; 16(10): 1014-27.
[http://dx.doi.org/10.1007/s10495-011-0625-x] [PMID: 21710254]
[http://dx.doi.org/10.1007/s10495-011-0625-x] [PMID: 21710254]
[88]
Li W, Zhang C, Du H, et al. Withaferin A suppresses the up-regulation of acetyl-coA carboxylase 1 and skin tumor formation in a skin carcinogenesis mouse model. Mol Carcinog 2016; 55(11): 1739-46.
[http://dx.doi.org/10.1002/mc.22423] [PMID: 26472150]
[http://dx.doi.org/10.1002/mc.22423] [PMID: 26472150]
[89]
Nagy Z, Cheung BB, Tsang W, et al. Withaferin A activates TRIM16 for its anti-cancer activity in melanoma. Sci Rep 2020; 10(1): 19724.
[http://dx.doi.org/10.1038/s41598-020-76722-x] [PMID: 33184347]
[http://dx.doi.org/10.1038/s41598-020-76722-x] [PMID: 33184347]
[90]
Siddharth S, Muniraj N, Saxena N, Sharma D. Concomitant inhibition of cytoprotective autophagy augments the efficacy of withaferin A in hepatocellular carcinoma. Cancers 2019; 11(4): 453.
[http://dx.doi.org/10.3390/cancers11040453] [PMID: 30934990]
[http://dx.doi.org/10.3390/cancers11040453] [PMID: 30934990]
[91]
Wang Y-X, Ding W-B, Dong C-WJT. J o P R. Withaferin A suppresses liver tumor growth in a nude mouse model by downregulation of cell signaling pathway leading to invasion and angiogenesis. Trop J Pharm Res 2015; 14(6): 1005-11.
[http://dx.doi.org/10.4314/tjpr.v14i6.10]
[http://dx.doi.org/10.4314/tjpr.v14i6.10]
[92]
Kuppusamy P, Nagalingam A, Muniraj N, Saxena NK, Sharma D. Concomitant activation of ETS-like transcription factor-1 and Death Receptor-5 via extracellular signal-regulated kinase in withaferin A-mediated inhibition of hepatocarcinogenesis in mice. Sci Rep 2017; 7(1): 17943.
[http://dx.doi.org/10.1038/s41598-017-18190-4] [PMID: 29263422]
[http://dx.doi.org/10.1038/s41598-017-18190-4] [PMID: 29263422]
[93]
Murugan S, Ameesh M, Shilpa S, Vishal BR. Study on the anticarcinogenic efficacy of withaferin-A in DEN induced hepatocellular carcinoma: morphology and histopathology. J Int J Health Sci 2015; 5: 273-82.
[94]
Shiragannavar VD, Gowda NGS, Kumar DP, Mirshahi F, Santhekadur PK. Withaferin A acts as a novel regulator of liver X receptor-α in HCC. Front Oncol 2021; 10: 628506.
[http://dx.doi.org/10.3389/fonc.2020.628506] [PMID: 33585254]
[http://dx.doi.org/10.3389/fonc.2020.628506] [PMID: 33585254]
[95]
Nishikawa Y, Okuzaki D, Fukushima K, et al. Withaferin A induces cell death selectively in androgen-independent prostate cancer cells but not in normal fibroblast cells. PLoS One 2015; 10(7): e0134137.
[http://dx.doi.org/10.1371/journal.pone.0134137] [PMID: 26230090]
[http://dx.doi.org/10.1371/journal.pone.0134137] [PMID: 26230090]
[96]
Roy RV, Suman S, Das TP, Luevano JE, Damodaran C, Withaferin A. steroidal lactone from Withania somnifera, induces mitotic catastrophe and growth arrest in prostate cancer cells. J Nat Prod 2013; 76(10): 1909-15.
[http://dx.doi.org/10.1021/np400441f] [PMID: 24079846]
[http://dx.doi.org/10.1021/np400441f] [PMID: 24079846]
[97]
Srinivasan S, Ranga RS, Burikhanov R, Han SS, Chendil D. Par-4-dependent apoptosis by the dietary compound withaferin A in prostate cancer cells. Cancer Res 2007; 67(1): 246-53.
[http://dx.doi.org/10.1158/0008-5472.CAN-06-2430] [PMID: 17185378]
[http://dx.doi.org/10.1158/0008-5472.CAN-06-2430] [PMID: 17185378]
[98]
Suman S, Das TP, Moselhy J, et al. Oral administration of withaferin A inhibits carcinogenesis of prostate in TRAMP model. Oncotarget 2016; 7(33): 53751-61.
[http://dx.doi.org/10.18632/oncotarget.10733] [PMID: 27447565]
[http://dx.doi.org/10.18632/oncotarget.10733] [PMID: 27447565]
[99]
Hahm ER, Singh SV. Cytoprotective autophagy induction by withaferin A in prostate cancer cells involves GABARAPL1. Mol Carcinog 2020; 59(10): 1105-15.
[http://dx.doi.org/10.1002/mc.23240] [PMID: 32743846]
[http://dx.doi.org/10.1002/mc.23240] [PMID: 32743846]
[100]
Munagala R, Kausar H, Munjal C, Gupta RC. Withaferin A induces p53-dependent apoptosis by repression of HPV oncogenes and upregulation of tumor suppressor proteins in human cervical cancer cells. Carcinogenesis 2011; 32(11): 1697-705.
[http://dx.doi.org/10.1093/carcin/bgr192] [PMID: 21859835]
[http://dx.doi.org/10.1093/carcin/bgr192] [PMID: 21859835]
[101]
Lee DH, Lim IH, Sung EG, et al. Withaferin A inhibits matrix metalloproteinase-9 activity by suppressing the Akt signaling pathway. Oncol Rep 2013; 30(2): 933-8.
[http://dx.doi.org/10.3892/or.2013.2487] [PMID: 23708780]
[http://dx.doi.org/10.3892/or.2013.2487] [PMID: 23708780]
[102]
Kim JE, Lee JY, Kang MJ, et al. Withaferin A inhibits helicobacter pylori-induced production of IL-1β in dendritic cells by regulating NF-κB and NLRP3 inflammasome activation. Immune Netw 2015; 15(6): 269-77.
[http://dx.doi.org/10.4110/in.2015.15.6.269] [PMID: 26770181]
[http://dx.doi.org/10.4110/in.2015.15.6.269] [PMID: 26770181]
[103]
Kim G, Kim TH, Hwang EH, Chang KT, Hong JJ, Park JH. Withaferin A inhibits the proliferation of gastric cancer cells by inducing G2/M cell cycle arrest and apoptosis. Oncol Lett 2017; 14(1): 416-22.
[http://dx.doi.org/10.3892/ol.2017.6169] [PMID: 28693185]
[http://dx.doi.org/10.3892/ol.2017.6169] [PMID: 28693185]
[104]
Okamoto S, Tsujioka T, Suemori S, et al. Withaferin A suppresses the growth of myelodysplasia and leukemia cell lines by inhibiting cell cycle progression. Cancer Sci 2016; 107(9): 1302-14.
[http://dx.doi.org/10.1111/cas.12988] [PMID: 27311589]
[http://dx.doi.org/10.1111/cas.12988] [PMID: 27311589]
[105]
Shi L-H, Wu X-J, Liu J-S, Gao Y-B. Withaferin A activates stress signalling proteins in high risk acute lymphoblastic leukemia. Int J Clin Exp Pathol 2015; 8(12): 15652-60.
[PMID: 26884834]
[PMID: 26884834]
[106]
Oh JH, Lee TJ, Kim SH, et al. Induction of apoptosis by withaferin A in human leukemia U937 cells through down-regulation of Akt phosphorylation. Apoptosis 2008; 13(12): 1494-504.
[http://dx.doi.org/10.1007/s10495-008-0273-y] [PMID: 19002588]
[http://dx.doi.org/10.1007/s10495-008-0273-y] [PMID: 19002588]
[107]
Malik V, Radhakrishnan N, Kaul SC, Wadhwa R, Sundar D. Computational identification of BCR-ABL oncogenic signaling as a candidate target of Withaferin A and Withanone. Biomolecules 2022; 12(2): 212.
[http://dx.doi.org/10.3390/biom12020212] [PMID: 35204712]
[http://dx.doi.org/10.3390/biom12020212] [PMID: 35204712]
[108]
Grover A, Shandilya A, Agrawal V, et al. Hsp90/Cdc37 chaperone/co-chaperone complex, a novel junction anti-cancer target elucidated by the mode of action of herbal drug Withaferin A. BMC Bioinformatics 2011; 12(1): 1-13.
[109]
Hou P, Liu D, Shan Y, et al. Genetic alterations and their relationship in the phosphatidylinositol 3-kinase/Akt pathway in thyroid cancer. Clin Cancer Res 2007; 13(4): 1161-70.
[http://dx.doi.org/10.1158/1078-0432.CCR-06-1125] [PMID: 17317825]
[http://dx.doi.org/10.1158/1078-0432.CCR-06-1125] [PMID: 17317825]
[110]
Verhey KJ, Gaertig J. The tubulin code. Cell Cycle 2007; 6(17): 2152-60.
[http://dx.doi.org/10.4161/cc.6.17.4633] [PMID: 17786050]
[http://dx.doi.org/10.4161/cc.6.17.4633] [PMID: 17786050]
[111]
Satelli A, Li S. Vimentin in cancer and its potential as a molecular target for cancer therapy. Cell Mol Life Sci 2011; 68(18): 3033-46.
[http://dx.doi.org/10.1007/s00018-011-0735-1] [PMID: 21637948]
[http://dx.doi.org/10.1007/s00018-011-0735-1] [PMID: 21637948]
[112]
Bargagna-Mohan P, Hamza A, Kim YE, et al. The tumor inhibitor and antiangiogenic agent withaferin A targets the intermediate filament protein vimentin. Chem Biol 2007; 14(6): 623-34.
[http://dx.doi.org/10.1016/j.chembiol.2007.04.010] [PMID: 17584610]
[http://dx.doi.org/10.1016/j.chembiol.2007.04.010] [PMID: 17584610]
[113]
Mei L, Zhang J, He K, Zhang J. Ataxia telangiectasia and Rad3-related inhibitors and cancer therapy: Where we stand. J Hematol Oncol Lett 2019; 12(1): 1-8.
[114]
Yap TA, Tan DSP, Terbuch A, et al. First-in-human trial of the oral ataxia telangiectasia and RAD3-Related (ATR) inhibitor BAY 1895344 in patients with advanced solid tumors. Cancer Discov 2021; 11(1): 80-91.
[http://dx.doi.org/10.1158/2159-8290.CD-20-0868] [PMID: 32988960]
[http://dx.doi.org/10.1158/2159-8290.CD-20-0868] [PMID: 32988960]
[115]
Yue P, Turkson J. Targeting STAT3 in cancer: How successful are we? Expert Opin Investig Drugs 2009; 18(1): 45-56.
[http://dx.doi.org/10.1517/13543780802565791] [PMID: 19053881]
[http://dx.doi.org/10.1517/13543780802565791] [PMID: 19053881]
[116]
Jing N, Tweardy DJ. Targeting Stat3 in cancer therapy. Anticancer Drugs 2005; 16(6): 601-7.
[http://dx.doi.org/10.1097/00001813-200507000-00002] [PMID: 15930886]
[http://dx.doi.org/10.1097/00001813-200507000-00002] [PMID: 15930886]
[117]
Xiu M-X, Liu Y-M. The role of oncogenic Notch2 signaling in cancer: A novel therapeutic target. Am J Cancer Res 2019; 9(5): 837-54.
[PMID: 31218097]
[PMID: 31218097]
[118]
Chu D, Zheng J, Wang W, et al. Notch2 expression is decreased in colorectal cancer and related to tumor differentiation status. Ann Surg Oncol 2009; 16(12): 3259-66.
[http://dx.doi.org/10.1245/s10434-009-0655-6] [PMID: 19653042]
[http://dx.doi.org/10.1245/s10434-009-0655-6] [PMID: 19653042]
[119]
O’Brien CS, Farnie G, Howell SJ, Clarke RB. Breast cancer stem cells and their role in resistance to endocrine therapy. Horm Cancer 2011; 2(2): 91-103.
[http://dx.doi.org/10.1007/s12672-011-0066-6] [PMID: 21761332]
[http://dx.doi.org/10.1007/s12672-011-0066-6] [PMID: 21761332]
[120]
Dolcet X, Llobet D, Pallares J, Matias-Guiu X. NF-kB in development and progression of human cancer. Virchows Arch 2005; 446(5): 475-82.
[http://dx.doi.org/10.1007/s00428-005-1264-9] [PMID: 15856292]
[http://dx.doi.org/10.1007/s00428-005-1264-9] [PMID: 15856292]
[121]
Heyninck K, Lahtela-Kakkonen M, Van der Veken P, Haegeman G, Vanden Berghe W. Withaferin A inhibits NF-kappaB activation by targeting cysteine 179 in IKKβ. Biochem Pharmacol 2014; 91(4): 501-9.
[http://dx.doi.org/10.1016/j.bcp.2014.08.004] [PMID: 25159986]
[http://dx.doi.org/10.1016/j.bcp.2014.08.004] [PMID: 25159986]
[122]
Oh JH, Kwon TK. Withaferin A inhibits tumor necrosis factor-α-induced expression of cell adhesion molecules by inactivation of Akt and NF-κB in human pulmonary epithelial cells. Int Immunopharmacol 2009; 9(5): 614-9.
[http://dx.doi.org/10.1016/j.intimp.2009.02.002] [PMID: 19236958]
[http://dx.doi.org/10.1016/j.intimp.2009.02.002] [PMID: 19236958]
[123]
Mohan R, Hammers H, Bargagna-mohan P, et al. Withaferin A is a potent inhibitor of angiogenesis. Angiogenesis 2004; 7(2): 115-22.
[http://dx.doi.org/10.1007/s10456-004-1026-3] [PMID: 15516832]
[http://dx.doi.org/10.1007/s10456-004-1026-3] [PMID: 15516832]
Article Metrics
![Wayfinder Image](/images/wayfinder.jpg)